Browsing by Author "DaSilva-Arnold, Sonia C."

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    Phenotyping acute and chronic atopic dermatitis-like lesions in Stat6VT mice identifies a role for IL-33 in disease pathogenesis
    (Springer, 2018-04) DaSilva-Arnold, Sonia C.; Thyagarajan, Anita; Seymour, Leroy J.; Yi, Qiaofang; Bradish, Joshua R.; Al-Hassani, Mohammed; Zhou, Hongming; Perdue, Nikolajs J.; Nemmeth, Val; Krbanjevic, Aleksandar; Serezani, Ana P. M.; Olson, Matthew R.; Spandau, Dan F.; Travers, Jeffrey B.; Kaplan, Mark H.; Turner, Matthew J.; Dermatology, School of Medicine
    The Stat6VT mouse model of atopic dermatitis (AD) is induced by T-cell-specific expression of a constitutively active form of the protein signal transducer and activator of transcription 6 (STAT6). Although AD-like lesions are known to develop in Stat6VT mice, this study was designed to determine if these mice develop acute and chronic phases of disease similar to humans. To address this, AD-like lesions from Stat6VT mice were harvested at two different timepoints relative to their onset. Lesions harvested within 1 week after development were defined as acute lesions, and those present for 1 month or more were defined as chronic lesions. Acute and chronic AD-like lesions from Stat6VT mice exhibited histologic findings and cytokine expression patterns similar to acute and chronic AD lesions in humans. Further analysis revealed increased levels of interleukin (IL)-33 transcripts in AD-like lesions compared to Stat6VT nonlesional and wild-type skin controls. Immunofluorescence also revealed increased numbers of IL-33+ keratinocytes in Stat6VT lesional skin and localized IL-33+ keratinocytes to a keratin 5+ subset. Furthermore, AD-like disease was more severe in IL-33-deficient Stat6VT mice compared to IL-33-sufficient Stat6VT mice. These studies suggest that Stat6VT mice can serve as a model of acute and chronic AD and that IL-33 may attenuate inflammation in this system.
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    Spatiotemporal assessments of dermal hyperemia enable accurate prediction of experimental cutaneous carcinogenesis as well as chemopreventive activity
    (American Association for Cancer Research, 2013) Konger, Raymond L.; Xu, Zhengbin; Sahu, Ravi P.; Rashid, Badri M.; Mehta, Shama R.; Mohamed, Deena R.; DaSilva-Arnold, Sonia C.; Bradish, Joshua R.; Warren, Simon J.; Kim, Young L.; Pathology and Laboratory Medicine, School of Medicine
    Field cancerization refers to areas of grossly normal epithelium that exhibit increased risk for tumor occurrence. Unfortunately, elucidation of the locoregional changes that contribute to increased tumor risk is difficult due to the inability to visualize the field. In this study, we use a noninvasive optical-based imaging approach to detail spatiotemporal changes in subclinical hyperemia that occur during experimental cutaneous carcinogenesis. After acute inflammation from 10 weeks of UVB irradiation subsides, small areas of focal hyperemia form and were seen to persist and expand long after cessation of UVB irradiation. We show that these persistent early hyperemic foci reliably predict sites of angiogenesis and overlying tumor formation. More than 96% of the tumors (57 of 59) that developed following UVB or 7,12-dimethylbenz(a)anthracene/phorbol 12-myristate 13-acetate (DMBA/PMA) treatment developed in sites of preexisting hyperemic foci. Hyperemic foci were multifocal and heterogeneously distributed and represented a minor fraction of the carcinogen-treated skin surface (10.3% of the imaging area in vehicle-treated animals). Finally, we also assessed the ability of the anti-inflammatory agent, celecoxib, to suppress hyperemia formation during photocarcinogenesis. The chemopreventive activity of celecoxib was shown to correlate with its ability to reduce the area of skin that exhibit these hyperemic foci, reducing the area of imaged skin containing hyperemic foci by 49.1%. Thus, we propose that a hyperemic switch can be exploited to visualize the cancerization field very early in the course of cutaneous carcinogenesis and provides insight into the chemopreventive activity of the anti-inflammatory agent celecoxib.
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    Topical Application of a Platelet Activating Factor Receptor Agonist Suppresses Phorbol Ester-Induced Acute and Chronic Inflammation and Has Cancer Chemopreventive Activity in Mouse Skin
    (PLoS, 2014-11) Sahu, Ravi P.; Rezania, Samin; Ocana, Jesus A.; DaSilva-Arnold, Sonia C.; Bradish, Joshua R.; Richey, Justin D.; Warren, Simon J.; Rashid, Badri; Travers, Jeffrey B.; Konger, Raymond L.; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Platelet activating factor (PAF) has long been associated with acute edema and inflammatory responses. PAF acts by binding to a specific G-protein coupled receptor (PAF-R, Ptafr). However, the role of chronic PAF-R activation on sustained inflammatory responses has been largely ignored. We recently demonstrated that mice lacking the PAF-R (Ptafr-/- mice) exhibit increased cutaneous tumorigenesis in response to a two-stage chemical carcinogenesis protocol. Ptafr-/- mice also exhibited increased chronic inflammation in response to phorbol ester application. In this present study, we demonstrate that topical application of the non-hydrolysable PAF mimetic (carbamoyl-PAF (CPAF)), exerts a potent, dose-dependent, and short-lived edema response in WT mice, but not Ptafr -/- mice or mice deficient in c-Kit (c-KitW-sh/W-sh mice). Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications. Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis. The ability of CPAF to suppress acute and chronic inflammatory changes in response to PMA application(s) was PAF-R dependent, as CPAF had no effect on basal or PMA-induced inflammation in Ptafr-/- mice. Moreover, c-Kit appears to be necessary for the anti-inflammatory effects of CPAF, as CPAF had no observable effect in c-KitW-sh/W-sh mice. These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development.
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    Topical Application of a Vitamin D Analogue Exacerbates Atopic Dermatitis and Induces the Atopic Dermatitis-like Phenotype in Stat6VT mice
    (Wiley, 2013) Turner, Matthew J.; DaSilva-Arnold, Sonia C.; Yi, Qiaofang; Mehrotra, Purvi; Kaplan, Mark H.; Travers, Jeffrey B.; Dermatology, School of Medicine
    Calcipotriene is a topical vitamin D3 analogue approved for the treatment of plaque and scalp psoriasis. We report the case of a 2-year-old boy whose atopic dermatitis (AD) flared in response to application of calcipotriene 0.005% cream and solution for a mistaken diagnosis of plaque and scalp psoriasis. We investigated whether the patient's eruption was secondary to an allergic contact dermatitis. In the Stat6VT mouse model of AD we tested whether calcipotriene could induce the otherwise-spontaneous AD-like phenotype. Closed patch testing was done on the patient with calcipotriene solution and cream, moisturizing cream, and 51% isopropanol. Stat6VT and wild-type (WT) mice were treated for 7 days with calcipotriene solution or vehicle (isopropanol) applied to the right and left upper back skin, respectively, after which mice were followed longitudinally for 10 weeks. Biopsy specimens from prior treatment sites were then collected for histology and RNA isolation. RNA was analyzed for interleukin (IL-4) expression using quantitative polymerase chain reaction. Patch testing was negative. Stat6VT mice, in contrast to WT mice, developed a persistent eczematous dermatitis at sites of calcipotriene application. Clinical and histologic features and high IL-4 transcript levels were consistent with the spontaneous AD-like phenotype seen in Stat6VT mice. At sites of active disease, calcipotriene can worsen a flare of AD. In Stat6VT mice, calcipotriene can induce the AD-like phenotype.